There are a variety of diseases which have an adverse impact on bone, including osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, loosening of bone prostheses and glucocorticoid treatment. A characteristic feature shared by each of these diseases is bone loss. In some cases, this bone loss is thought to result from an imbalance between bone resorption (breakdown) and bone formation. Bone loss occurs in a wide range of subjects including aging men and women, post-menopausal women, patients who have undergone hysterectomy, patients who are undergoing or have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and patients having gonadal dysgenesis.
Peak bone mass is usually attained between the ages of 35 and 40 in humans. Thereafter, a slight imbalance occurs between the processes of bone formation by osteoblasts and bone resorption by osteoclasts. This imbalance continues throughout the remainder of the individual's life, at the rate of about 10% per year on the average. However, the rate of bone turnover differs from site to site. For example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk. This imbalance is increased in some diseases, resulting in an even more rapid rate of bone loss, and significant associated problems.
The cells which resorb bone, osteoclasts, and those which make bone, osteoblasts, have very precise functions. The balance between their activities is critical to the maintenance of the skeletal system. Osteoclasts are large, multinucleated cells. They have high capacities for the synthesis and storage of enzymes, including acid hydrolases and carbonic anhydrase isoenzyme II. Activation of osteoclasts to resorb bone is generally thought to involve release of organic acids and membrane-bound packages of enzymes onto the bone surface. This requires elaboration next to the bone surface of a specialized region of the plasma membrane, the ruffled border. In this region the osteoclast's prepackaged, membrane-bound enzymes can fuse with the plasma membrane and be released onto the bone surface in a confined extracellular space. Degradation of the inorganic and organic tissue occurs in this area. The products of resorption are then taken up via endocytosis for additional intracellular processing within cytoplasmic vacuoles. Osteoblasts are mononuclear cells that express and secrete a number of enzymes and structural proteins of the bone matrix, including Type-I collagen, osteocalcin, osteopontin and alkaline phosphatase (Stein G. et al. Curr Opin Cell Biol (1990) 2: 1018–27). Osteoblasts also synthesize a number of growth regulatory peptides which are stored in the bone matrix, and are presumably responsible for normal bone formation.
Unchecked, bone loss can lead to osteoporosis or osteopenia. Osteopenia is reduced bone mass due to a decrease in the rate of osteoid synthesis to a level insufficient to compensate for normal bone lysis. Osteoporosis is a major debilitating disease whose prominent feature is the loss of bone mass (decreased density and enlargement of intertrabecular spaces) without a reduction in bone volume, producing porosity and fragility. Osteoporosis and osteopenia are present in both aging men and women, due to age-related bone loss. There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
There are currently no satisfactory pharmaceutical approaches to managing bone loss. Bone deterioration associated with post-menopausal osteoporosis has been decreased or prevented with hormones. Although the administration of estrogens has beneficial effects on bone, even when given at very low levels, long-term estrogen therapy has been implicated in a variety of disorders. These include an increase in the risk of uterine and breast cancer, vaginal bleeding, and endometrial hyperplasia, and cause many women to avoid this form of treatment. Recently suggested therapeutic regimens which seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, may be linked to negative cardiovascular effects. Concerns over the significant undesirable effects associated with estrogen therapy, and the limited ability of estrogens to reverse existing bone loss, support the need to develop alternative therapy for bone loss that generates the desirable effects on bone but does not cause undesirable effects.
Antiestrogens, which interact with the estrogen receptor, have been used in women suffering from the effects of osteoporosis, for whom estrogen therapy is not appropriate. This form of therapy has had limited success, perhaps due to the fact that these compounds generally display a mixed agonist/antagonist effect. That is, although these compounds can antagonize estrogen interaction with the receptor, the compounds themselves may cause estrogenic responses in those tissues having estrogen receptors. Therefore, some antiestrogens, when administered alone, are subject to the same adverse effects associated with estrogen therapy. A further disadvantage to both estrogen and antiestrogen therapy is that neither has been shown to promote re-growth of lost bone.
Treatments used for bone loss in both men and women include vitamin and mineral supplementation with calcium and vitamin D. This approach has shown limited effectiveness in treating osteopenias or osteoporosis and the benefits are limited in treating and preventing bone loss. Growth of new bone is not possible with this form of treatment. Bone loss in men is also treated with androgens such as testosterone. Treatment with testosterone also displays antagonistic effects as with estrogen therapy in women, and can lead to baldness, acne, lowering of HDL cholesterol (the “good” cholesterol) and raising of LDL cholesterol (the “bad” cholesterol), and importantly may be associated with an increased risk of prostate cancer and benign prostatic hyperplasia.
Treatment with bisphosphonates such as alendronate, currently marketed by Merck & Co., Inc. as FOSAMAX®, has also been successful in inhibiting bone loss and increasing bone density. However, bisphosphonates have low bioavailability and their administration must avoid food interactions. Treatment with shots or intranasal Calcitonin and low dose PTH (parathyroid hormone) shots have also been employed in an effort to inhibit bone loss and treat or prevent osteoporosis. A detractor from the possible benefits of treatment with calcitonin is the associated high rate of allergic reaction in subjects.
In view of the deficiencies of the currently-available therapies, it is desirable to have new therapeutic methods and agents that promote bone deposition and growth.